Haemophilia A is an inherited bleeding disorder caused by deficiency or dysfunction of coagulation Factor VIII (FVIII) activity. The clinical manifestation is not on primary haemostasis—formation of the blood clot occurs normally—but the clot is unstable due to a lack of secondary thrombin formation. The disease is treated by intravenous injection of coagulation Factor FVIII which is either isolated from blood or produced recombinantly.
Current treatment recommendations are moving from traditional on-demand treatment towards prophylaxis. The circulatory half life of endogenous FVIII is 12-14 hours and prophylactic treatment is thus to be performed several times a week in order to obtain a virtually symptom-free life for the patients. IV administration is for many, especially children and young persons, associated with significant inconvenience and/or pain. There is thus a need in the art for novel Factor VIII products with Factor VIII activity that are preferably homogenous in structure, preferably safe and preferably having a significantly prolonged circulatory half life in order to reduce the number of Factor VIII administration per week. There is furthermore a need in the art for relatively simple methods for obtaining and producing such molecules.
PEGylation of Factor VIII in order to prolong circulatory half life is known in the art. It has however been an obstacle to obtain safe products having a homogenous structure as well as a significantly improved circulatory half life. The available methods of producing conjugated Factor VIII molecules are often laborious, and/or tend to result in low yields and/or products that are not homogenous in structure. The use of artificially engineered O-linked glycosylation sites for obtaining therapeutic proteins having a prolonged circulatory half life of therapeutic proteins has been suggested in WO2008011633, however, no conjugated Factor VIII molecules are disclosed therein.